The Role of Calcium Signalling in Autophagy

Chehab, Tala (2018). The Role of Calcium Signalling in Autophagy. PhD thesis The Open University.

Abstract

Autophagy is a catabolic process that is important for degradation of cellular components, and for cell survival, and has also been associated with pathological disorders and tumour growth. Autophagy is a complex process; many factors and messengers converge to control steps along the autophagic pathway. Ca2+ has been proposed to regulate autophagy. However, Ca2+ has been proposed to be both pro- and anti-autophagic. To better understand how Ca2+ has these opposing effects, this study investigated in what ways particular sources of Ca2+, and the characteristics of Ca2+ signals impacted on autophagy.

The fundamental need for Ca2+ in the activation of autophagy was demonstrated by loading cells with an exogenous Ca2+ buffer, which prevented various stimuli from triggering autophagy.

Autophagy could be activated by inhibiting the transfer of Ca2+ from the endoplasmic reticulum to the mitochondrial matrix. This was achieved by expressing an enzyme that prevented Ca2+ release from inositol 1,4,5-trisphosphate receptors, inhibition of mitochondrial respiration, and knockdown of the mitochondrial Ca2+ uniporter. The triggering of autophagy under these conditions was due to reduced cellular ATP levels. These data suggest that Ca2+ signals arising from InsP3Rs suppress autophagy.

Additional studies used a well-characterised Ca2+ transport pathway to generate cellular Ca2+ signals, and examined their ability to trigger autophagy. This pathway, known as ‘store-operated Ca2+ entry’ (SOCE), was activated by depleting endoplasmic reticulum Ca2+ stores using inhibitors of sarco/endoplasmic reticulum ATPases (SERCA). It was found that sustained cellular Ca2+ signals arising via chronic inhibition of SERCA were pro-autophagic. The activation of autophagy absolutely required the presence of extracellular Ca2+, and was not due to cellular stress. Using pharmacological inhibition of various Ca2+-sensitive kinases, it was found that at least part of the autophagy that occurred during SOCE was due to activation of Ca2+/calmodulin-dependent kinase kinase-β (CaMKK-β, also known as CaMKK-2).

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